Genetics and Diet Regulate Vitamin A Production via the Homeobox Transcription Factor ISX

Glenn P Lobo,Jaume Amengual,Diane Baus,Ramesh A Shivdasani,Derek Taylor,Johannes Von Lintig

doi:10.1074/jbc.m112.444240

Glenn P Lobo, Jaume Amengual + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m112.444240

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Abstract

Low dietary intake of β-carotene is associated with chronic disease and vitamin A deficiency. β-Carotene is converted to vitamin A in the intestine by the enzyme β-carotene-15,15'-monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation. Considerable variability for this key step in vitamin A metabolism, as reported in the human population, could be related to genetics and individual vitamin A status, but it is unclear how these factors influence β-carotene metabolism and vitamin A homeostasis. Here we show that the intestine-specific transcription factor ISX binds to the Bcmo1 promoter. Moreover, upon induction by the β-carotene derivative retinoic acid, this ISX binding decreased expression of a luciferase reporter gene in human colonic CaCo-2 cells indicating that ISX acts as a transcriptional repressor of BCMO1 expression. Mice deficient for this transcription factor displayed increased intestinal BCMO1 expression and produced significantly higher amounts of vitamin A from supplemental β-carotene. The ISX binding site in the human BCMO1 promoter contains a common single nucleotide polymorphism that is associated with decreased conversion rates and increased fasting blood levels of β-carotene. Thus, our study establishes ISX as a critical regulator of vitamin A production and provides a mechanistic explanation for how both genetics and diet can affect this process.

Highlights

Dietary ␤-carotene is the natural precursor of vitamin A
As each of the six Bcmo1 promoter fragments overlapped with neighboring fragments, we reasoned that the putative binding site for ISX might encompass a region shared by fragments 2 and 3 (Fig. 1A)
We identify a binding site for ISX in the Bcmo1 promoter and provide evidence that ISX is a transcriptional repressor of Bcmo1 expression

Summary

Introduction

Dietary ␤-carotene is the natural precursor of vitamin A. ␤-Carotene is converted to vitamin A in the intestine by the enzyme ␤-carotene-15,15؅monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation Considerable variability for this key step in vitamin A metabolism, as reported in the human population, could be related to genetics and individual vitamin A status, but it is unclear how these factors influence ␤-carotene metabolism and vitamin A homeostasis. Upon induction by the ␤-carotene derivative retinoic acid, this ISX binding decreased expression of a luciferase reporter gene in human colonic CaCo-2 cells indicating that ISX acts as a transcriptional repressor of BCMO1 expression. Mice deficient for this transcription factor displayed increased intestinal BCMO1 expression and produced significantly higher amounts of vitamin A from supplemental ␤-carotene. Our study establishes ISX as a critical regulator of vitamin A production and provides a mechanistic explanation for how both genetics and diet can affect this process

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